Nuclear decoupling is part of a rapid protein-level cellular response to high-intensity mechanical loading

Abstract

Studies of cellular mechano-signaling have often utilized static models that do not fully replicate the dynamics of living tissues. Here, we examine the time-dependent response of primary human mesenchymal stem cells (hMSCs) to cyclic tensile strain (CTS). At low-intensity strain (1\u2009h, 4% CTS at 1\u2009Hz), cell characteristics mimic responses to increased substrate stiffness. As the strain regime is intensified (frequency increased to 5\u2009Hz), we characterize rapid establishment of a broad, structured and reversible protein-level response, even as transcription is apparently downregulated. Protein abundance is quantified coincident with changes to protein conformation and post-translational modification (PTM). Furthermore, we characterize changes to the linker of nucleoskeleton and cytoskeleton (LINC) complex that bridges the nuclear envelope, and specifically to levels and PTMs of Sad1/UNC-84 (SUN) domain-containing protein 2 (SUN2). The result of this regulation is to decouple mechano-transmission between the cytoskeleton and the nucleus, thus conferring protection to chromatin. Cells must be robust to the mechanical demands of their environments. Here, Gilbert et al. expose cells to high-intensity strain cycling and use proteomics to identify a protein, SUN2, that behaves as a strain-induced breakpoint that can decouple the nucleoskeleton from the cytoskeleton.